Viral infections cause considerable discomfort, disease and can be fatal. Viruses such as herpes simplex viruses (HSV-1 and HSV-2), cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), influenza viruses, human lymphotrophic viruses (e.g., HTLV-1) and human immunodeficiency viruses (e.g., HIV-1) result in significant morbidity and mortality. HSV-1 and HSV-2 are associated with inflammation and lesions of the skin and mucosal membranes, including cold sores, fever blisters and genital herpes lesions. VZV causes shingles and EBV is associated with mononucleosis. Influenza viruses cause flu symptoms and can be fatal. HIV causes acquired immunodeficiency which debilitates and kills infected individuals. Although these viruses may remain latent in some cells and for varying periods of time, generally viral replication results in irreversible destruction of the infected cell producing different clinical manifestations of the diseases they cause.
Antiviral and anti-inflammatory activities of aliphatic alcohols having from 20 to 32 carbons are known in the art as disclosed in U.S. Pat. No. 4,874,794, U.S. Pat. No. 5,071,879, U.S. Pat. No. 5,166,219, U.S. Pat. No. 5,194,451 and U.S. Pat. No. 5,534,554. Compositions containing aliphatic alcohols and related compounds having therapeutic activities are disclosed therein.
A C22 aliphatic alcohol, n-docosanol, suspended in a surfactant exhibits potent antiviral activity against viruses including herpes simplex virus, HIV-1 and respiratory syncytial virus in vitro and Friend virus in vivo (Katz, D. H., et al., Proc. Natl. Acad. Sci. USA 88:10825-10829, 1991; U.S. Pat. No. 5,534,554). Although the mechanism for this viral inhibition is unknown, n-docosanol does not inactivate the virus directly and thus is unlike C10 to C18 unsaturated alcohols that exhibit detergent-like antiviral activity (Katz, D. H., et al., Proc. Natl. Acad. Sci. USA 88:10825-10829, 1991; Snipes, W. et al., Antimicrob. Agents Chemother. 11:98-104, 1977). Progressive binding and uptake of n-docosanol by cells may account for its antiviral activity because pre-incubation of cells with the alcohol produces optimal antiviral activity. During incubation, 70% of the cell-associated n-docosanol is found in cell membranous components and the remainder is associated with soluble cell fractions (Katz, D. H., et al., Proc. Natl. Acad. Sci. USA 88:10825-10829, 1991). Cell membrane incorporation of n-docosanol does not inhibit virus binding to the cell surface. Instead, early viral protein synthesis is inhibited more than 80% and viruses do not localize to nuclei (Marcelletti, J. F. et al., Drugs of the Future 17(19): 879-882, 1992). Although intracellular metabolic conversions of n-docosanol may account for its antiviral activity (Katz, D. H. et al., Annals N.Y. Acad. Sciences, 724:472-488, 1994), the alcohol is not cytotoxic in concentrations up to 300 mM.
Inactivation of viruses has been reported using C14 to C20 unsaturated long chain alcohols having one to four unsaturated bonds. The most effective was .gamma.-linolenyl alcohol, a C18 alcohol with double bonds at positions 6, 9 and 12; whereas a C18 alcohol with one cis double bond and a C20 alcohol with four double bonds were significantly less effective (Sands et al., Antimicrob. Agents & Chemother. 15:67-73, 1979). Compositions containing oleic acid (C18, one double bond) have been reported as effective for anti-herpes virus agents (PCT patent application WO 9602244A1).
Some compounds that are structurally related to long-chain aliphatic alcohols also have been associated with antiviral activity. For example, U.S. Pat. No. 4,513,008 discloses the virucidal activity of C20 to C24 linear polyunsaturated acids, aldehydes or alcohols having five to seven double bonds. Compounds having a long chain fatty acyl group, containing at least three or four unsaturated bonds, attached to a nucleoside or nucleoside analogue are disclosed as antiviral treatments in U.S. Pat. No. 5,216,142. Related U.S. Pat. No. 5,276,020 discloses antiviral compounds having a C16, C18 or C20 long chain fatty acid group attached to a nucleoside analogue and a method of treating virus infection using these compounds.
Biological activity useful for treating tumors, protozoal and fungal diseases, autoimmune disease and bone marrow damage has been attributed to phospholipids having erucyl- and brassidyl-side chains, such as erucylphosphocholine (U.S. Pat. No. 5,436,234).
Although some long chain fatty alcohols and fatty acids affect cellular growth, such effects are presently ill-defined. For example, n-hexacosanol, a C26 alcohol, promotes neuronal growth whereas other long chain fatty n-alcohols containing 16, 20, 22, 24 and 30 carbon atoms do not (Borg, J. et al., FEBS Lett. 213(2):406-410, 1987). Docosahexaenoic acid, a C22 fatty acid having six double bonds, is concentrated in the central nervous system and the retina although its physiological role has not been defined (Bazan, N., Prog. Clin. Biol. Res. 312:95-112, 1989).
Antiviral activity has been reported for liposomal AL721, a mixture of neutral glycerides, phophatidylcholine and phosphatidylethanolamine (Antonian, L. et al., Neurosci. Biobehav. Rev. 11:399-413, 1987). Antimicrobial compositions for topical treatment containing a C15 glycerol monoester of lauric acid or a polyhydric alcohol monoester of lauric acid with a mixture of fatty acids (C10 capric and C8 caprylic acids) are disclosed in U.S. Pat. No. 5,208,257.
A method of preventing or reducing skin irritation by applying a protective agent containing polymers of C12 to C26 fatty acids prior to exposure to an allergenic agent is disclosed in U.S. Pat. No. 4,076,799. The preferred polymers have two to four carboxy or carboxyl salt groups, preferably the triethanolamine salt of dimerized linoleic acid or its saturated derivative. Other anti-inflammatory polymers containing aromatic heterocyclic residues or acyl residues in homopolymers or heteropolymers (e.g., vinyl esters of C8 to C18 fatty acids; m.w. 2,000 to 1,000,000) and having greater activity than the component monomers have been disclosed in U.S. Pat. No. 3,946,035.
Therapeutic treatment of herpes lesions using topically administered compositions containing an anesthetic, a surfactant and a topical carrier is disclosed in U.S. Pat. No. 5,380,754. A method of treating inflammation by topically applying ethyl-cis,cis(9,12)octadecadienoate (ethyl linoleate) is disclosed in U.S. Pat. No. 4,025,645 as a cold sore treatment.
The present invention discloses antiviral and cytotoxic effects of compounds related to long-chain aliphatic alcohols, including alkanes, alcohols, amides and long-chain fatty acids, and particularly compounds related to n-docosanol. These related compounds having antiviral activity include n-docosane, n-docosanoic acid, stearic acid, erucyl alcohol, erucamide and brassidyl alcohol. Moreover, the optimal ratio of surfactant to active ingredient for formulating an effective antiviral and/or cytotoxic suspension with these compounds or with n-docosanol is disclosed. These compounds and formulations are useful in antiviral preventive compositions and treatment therapeutics.